Synthesis of Letrozole

In vivo, letrozole (3) was efficacious in two animal models. One was a postmenopausal hormone-dependent breast cancer mouse model, the other was a dimethylbenz[a]-anthracene (DMBA)-induced mammary carcinoma rat model. 

In terms of pharmacokinetics, letrozole is well absorbed following 2.5-mg oral administration in healthy postmenopausal women. The maximum plasma concentration of 

(1998). Her-2, The Making of Herceptin, a Revolutionary Treatment for Breast Cancer, Random House, New York. 

Crotty, S. (2001). Ahead of the Curve, David Baltimore s Life in Science, University of California Press, Berkeley. 

Vasella, D. and Slater, R. (2003). Magic Cancer Bullet, Plow a Tiny Orange Pill Is Rewriting Medical History, Harper Business, New York. 

---

The synthesis of letrozole (3) is quite simple (Scheme 3.5). An Sn2 displacement of 4-bromomethyl-benzonitrile (25) with imidazole was carried out in methylene chloride at room temperature to produce adduct 26. Deprotonation of 26 in DMF using potassium t-butoxide was followed by addition of para-fluorobenzonitrile. The S Ar reaction afforded letrozole (3) as an oil. In order to make the crystalline drug, a hemisuccinate was prepared, which has a melting point of 149-150°C. 

---